Prostaglandin A{HD 2 {B analogs

ABSTRACT

Prostaglandin A compounds with a methyl or an ethyl substituent at the C-15 position are disclosed. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins A.

United States Patent Bundy et al.

lll] 3,919,286

[ Nov. 11, 1975 PROSTAGLANDIN A ANALOGS Inventors: Gordon L. Bundy; John E. Pike,

both of Kalamazoo. Mich.

Assignee: The Upjohn Company, Kalamazoo.

Mich.

Filed: May 1, 1974 Appl. No.: 465,882

Related U.S. Application Data Continuation of Ser. No. 238.848. Sept. l3. I972. abandoned, which is a continuation of Ser. No.

72.l(l5. Sept. l4. 1970. abandoned.

U.S. Cl... 260/468 D; 260/2ll R; 260/2472 R; 260/268 R. 260/2436 S; 260/3263; 260/429.9; 260/439 R. 260/448 R; 260/50l.l;260/50l.l5;260/50l.17;

260/50l.2; 260/514 D; 424/305; 424/3 l7 [51] Int. Cl. C02C 01/38: C07C 09/74 Primary Examiner-Robert Gerstl Arlurne). Agent. or Firm-Earl C. Spaeth [57] ABSTRACT Prostaglandin A compounds with a methyl or an ethyl substituent at the C-l5 position are disclosed. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins A.

7 Claims, No Drawings PROSTAGLANDIN A ANALOGS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of copending application Ser. No. 288,848, filed Sept. 13, 1972, and now abandoned, which is a continuation of copending application Ser. No. 72,105, filed Sept. l4, I970, and now abandoned.

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, to novel methods for producing those, and to novel chemical intermediates useful in those processes. In particular, this invention relates to novel derivatives of prostanoic acid which has the following structure and atom numbering:

l 4 1 mNj/iN /z Various derivatives of prostanoic acid are known in the art. These are called prostaglandins. See, for example, Bergstrom et al., Pharmacol. Rec. 20, l (1968),

and references cited therein. For example, prostaglandin A (PGA has the following structure:

COOH "W\/ a H OH Prostaglandin A (PGA has the following structure:

PGA has the following structure:

Prostaglandin E, (PGE has the following structure:

0 COOH VI H -0H Prostaglandin F m (PGFh) has the following structure:

Prostaglandins E and F corresponding to PGA PGA and l3,l4-dihydro-PGA, are also known.

In formulas II to VII, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring. The side-chain hydroxy at C- l 5 in formulas II to VII is in S configuration. See Nature, 2l2, 38 (1966) for discussion of the stereochemistry of the prostaglandins.

Molecules of the known prostaglandins each have several centers of asymmetry, and can exist in racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e.. the dextrorotatory and levorotatory forms. As drawn, formulas II to VII each represent the particular optically active form of the prostaglandin which is obtained from certain mammalian tissues, for example. sheep vesicular glands, swine lung, or human seminal plasma, or by carbonyl and/or double bond reduction or dehydration of a prostaglandin so obtained. See, for example, Bergstrom et al., cited above. The mirror image of each of formulas I] to VII would represent the other enantiomer of that prostaglandin. The racemic form of a prostaglandin would contain equal numbers of both enantiomeric molecules, and one of formulas II to VII and the mirror image of that formula would both be needed to represent correctly the corresponding racemic prostaglandin. For convenience hereinafter. use of the terms PGA, PGA PGA;, l3,I4-dihydro-PGA, PGE. PGE- PGE and dihydro-PGE will mean the optically active form of that prostaglandin with the same absolute configuration as PGE obtained from mammalian tissues. When reference to the racemic fon'n of one of those prostaglandins is intended, the work racemic" will preceed the prostaglandin name, thus. racemic PGA, or racemic PGE,

Each of the novel prostanoic acid derivatives of this invention is encompassed by one of the following formulas or by the combination of that formula and its mirror image:

In formulas VIII and IX, R is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacologically acceptable cation, R is methyl or ethyl, and X is CH CH 0r trans-CH=CH, and both Y and Z are -CH CH or X is trans-CH=CH, Y is cis-CH=)t CH, and Z is CH CH or cis-CH=CH. In formula VII] the configuration of the hydroxy at C-l is S as in the known prostaglandins of formulas ll to VII. ln formula [X the hydroxy at C-l5 is in the unnatural R or epi configuration. See J. Chem. Education, 41, 1 16 (1964), for discussion of S and R configurations.

A significant characteristic of all of the known prostaglandins is the secondary hydroxy group at C-l5, i.e., the atom grouping Prostaglandins obtained from animal tissues always contain that atom grouping. In striking contrast, each of the novel prostancic acid derivatives of this invention has a tertiary hydroxy group at C- l 5 i.e., the atom groupmg or the corresponding R or epi configuration grouping wherein R is methyl or ethyl. Thus, these novel pros tanoic acid derivatives may conveniently be designated l5-methyl-prostaglandins A or lS-ethyl-prostagladins A, e.g., lS-mcthyl-PGA, or l5-ethyl-l5(R)-PGA As in the case of formulas 11 to VII, formulas VIII and [X are each intended to represent optically active prostanoic acid derivatives with the same absolute configuration as PGE obtained from mammalian tissues. The novel prostanoic acid derivatives of this invention also include the corresponding racemic compounds. One of formulas Vlll or IX plus the mirror image of that formula are necessary in combination to describe a racemic compound. For convenience hereinafter, when the word racemic preceeds the name of one of the novel prostanoic acid derivatives of this invention, the intent is to designate a racemic compound represented by the combination of the appropriate formula Vlll or [X and the mirror image of that formula. When the word racemic does not preceed the compound name, the intent is to designate an optically active compound represented only by the appropriate formula Vlll or IX and with the same absolute configuration as PGE, obtained from animal tissues.

PGA, PGA PGA and l3,l4-dihydro-PGA i.e., the compounds of formulas 11, [I], IV, and V, respectively, and their esters and pharmacologically acceptable salts are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., cited above, and references cited therein. See also British Specifications 1,097,157 and 1,097,533.

For example, these known prostaglandins A are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 pg. to about 500 pg. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

Also. these known prostaglandins A are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 pg. per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 pg. per kg. of body weight total per day.

Also, these known prostaglandins A increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte content of the urine. Therefore, these compounds are useful in managing cases of renal disfunction, especially those involving blockage of the renal vascular bed. lllustratively, the compounds are useful to alleviate and correct cases of edema resulting, for example, from massive surface burns, and in the management of shock. For these purposes, the compounds are preferably first administered by intravenous injection at a dose in the range 10 to 1000 pg. per kg. of body weight or by intravenous infusion at a dose in the range 0.1 to 20 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, intramuscular, or subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

The novel IS-methyl and 15-ethyl prostaglandin A analogs encompassed by formulas Vlll and 1X each cause the same biological responses described above for the known prostaglandins A, and each of these novel PGA analogs is useful for the above-described pharmacological purposes, and is used for those purposes as described above. However, each of these l5- methyl and l5-ethyl prostaglandin A analogs is surprisingly and unexpectedly more useful than the corresponding known prostaglandin for at least one of the pharmacological purposes described above because for that purpose the analog is more potent and has a substantially longer duration of activity. For that reason, fewer and smaller doses of these prostaglandin analogs are needed to attain the desired pharmacological results.

The novel prostaglandin A analogs encompassed by formulas VIII and IX are used as described above in free acid form, in alkyl ester form, or in pharmacologically acceptable salt form. When the ester form is used, any alkyl ester can be used wherein the alkyl moiety contains one to 8 carbon atoms, inclusive, i.e., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptable salts of these prostaglandin analogs useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.

Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium and potas- 5 sium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about l8 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4- dimethylpiperazine, 2 -methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, Z-aminol-butanol, 2-amino-2-ethyl-l ,3-propanediol, 2-amino- 2-methyll -propanol, tris( hydroxymethyl )aminomethane, N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine, galactamine, N-methylglucamine, N- methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the novel prostaglandin analogs are administered in various ways for various purposes, e.g., intravenously, intramuscularly, and subcutaneously.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility to use the free acid form or the pharmacologically acceptable salt form. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used.

The novel l5-methyl and l5-ethyl prostaglandins A of formulas VIII and IX wherein R, is hydrogen or alkyl of one to 8 carbon atoms, inclusive, are prepared by the reactions defined in Chart A. In Chart A, R X, Y, and Z are as defined above, and R is hydrogen or alkyl of one to 8 carbon atoms, inclusive.

These reactions in Chart A are dehydrations. Any of the known substantially neutral dehydrating agents is used for these reactions. Preferred dehydrating agents are mixtures of at least an equivalent amount of a carbodiimide and a catalytic amount of a copper(ll) salt. Especially preferred are mixtures of at least an equivalent amount of dicyclohexylcarbodiimide and a catalytic amount of cpper(ll) chloride. An equivalent amount of a carbodiimide means one mole of the carbodiimide for each mole of the formula x or Xll reactant. To ensure completeness of the reaction, it is advantageous to use an excess of the carbodiimide, i.e., 1.5 to or even more equivalents of the carbodiimide.

6 CHART A The dehydration is advantageously carried out in the presence of an inert organic diluent which gives a homogeneous reaction mixture with respect to the formula X or Xll reactant and the carbodiimide. Diethyl ether is a suitable diluent.

[t is advantageous to carry out the dehydration in an atmosphere of an inert gas, e.g., nitrogen helium, or argon.

The time required for the dehydration will depend in part on the reaction temperature. With the reaction temperature in the range 20 to 30 C the dehydration usually takes place in about 40 to hours.

The formula XI or Xlll product is isolated by methods known in the art, e. g., filtration of the reaction mixture and evaporation of the filtrate. The product is then purified by methods known in the art, advantageously by chromatography on silica gel.

The formula X and Xll reactants are prepared as described in US, Pat. No. 3,728,382, which is incorporated herein by reference. The racemic reactants of formulas X and Xll and the mirror images of those formulas, wherein X is trans-CH=CH and Y and Z are cis-CH=CH are not described in said US. Patent but are prepared as described therein from racemic PGE or the alkyl esters of racemic PGE compounds which are known in the art or are prepared by methods known in the art. See, for example, Axen, Chemical Communications, 602 (I970). All of the other reactants encompassed by formulas X and Xll are described in said US. Patent.

When a formula X] or Xlll product wherein R is hydrogen is prepared as described above, and an alkyl ester of that acid is desired, esterification is advantageously accomplished by interaction of the acid with the appropriate diazohydrocarbon. For example, when 7 diazomethane is used, the methyl esters are produced. Similar use of diazoethane, diazobutane, and 1-dia2o-2- ethylhexane, for example, gives the ethyl, butyl, and 2- ethylhexyl esters, respectively.

Esteriflcation with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent. preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete, the solvent is removed by evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions. John Wiley & Sons, lnc., New York, N.Y., Vol. 8. pp. 389394 (1954).

An alternative method for esterification of the carboxyl moiety of the formula X] or Xlll acid comprises transformation of said acid to the corresponding silver salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, and the like. The silver salts are prepared by conventional methods, for example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of silver nitrate.

The novel formula Vlll or lX acids (R, is hydrogen) are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

The invention can be more fully understood by the following examples.

EXAMPLE 1 lS-Methyl-PGA; Methyl Ester A mixture of l5-methyl-PGE methyl ester (6 mg), dicyclohexylcarbodiimide (20 mg), copper(ll) chloride dihydrate (2 mg.), and diethyl ether (2 ml.) is stirred under nitrogen at 25 C. for l6 hours. Then, additional dicyclohexylcarbodiimide (20 mg.) is added, and the mixture is stirred an additional 32 hours at 25 C. under nitrogen. The resulting mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed by preparative thin layer chromatography with the A-IX system to give IS-methyl-PGA methyl ester; UV. absorption peak (ethanol solution) at 2]? ma.

EXAMPLE 2 l5-Methyl-PGA A mixture of l5-methyl-PGE (1.00 g.), dicyclohexylcarbodiimide (3.00 g.), copper(l]) chloride (300 mg.), and diethyl ether (300 ml.) is stirred at 25 C. under nitrogen for 24 hours. The, additional dicyclohexylcarbodiimide (3.00 g.) is added, and the mixture is stirred an additional 24 hours at 25 C. under nitrogen. The resulting mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 300 g. of silica gel, eluting with 2 l. of a gradient of 25l00% ethyl acetate in Skellysolve B (a mixture of isomeric hexanes). The eluate fractions containing the desired product as shown by TLC (A-IX) are combined and evaporated under reduced pressure to give l5-methyl-PGA Following the procedure of Example 1, l5-methyl- PGE IS-ethyI-PGE IS-ethyl-PGE l5-methyl-PGE I5-ethyl-PGE IS-methyI-dihydro-PGE and l5-ethyldihydro-PGD are dehydrated to give IS-methyl-PGA lS-ethyl-PGA l5-ethyl-PGA l5-methyl-PGA;, l5- ethyl-PGA lS-methyl-l3,14-dihydro-PGA and 15- ethyl-13,1 4-dihydro-PGA respectively.

Also following the procedure of Example 2, the racemic forms of IS-methyl-PGE IS-ethyI-PGE l5- methyl-PGE l5-ethyl-PGE l5-methyl-PGE l5- ethyl-PGE IS-methyldihydro-PGE and IS-ethyldihydro-PGE are each dehydrated to given the corresponding racemic form of the l5-methyl or l5-ethyl prostaglandin A.

Also following the procedure of Example 2, IS-methyl-l5(R)-PGE l5-ethyl-lS(R)-PGE,, IS-methyll5(R)-PGE l5-ethyl-l5(R)-PGE l5-methyl-15(R)- PGE l5-ethy1-l5(R)-PGE lS-methyl-dihydrol5(R)-PGE,, l5-ethyl-dihydro-l5(R)-PGE and the racemic forms of each of those are each dehydrated to the corresponding optically active or racemic form of the IS-methyl or lS-ethyl prostaglandin A.

Also following the procedure of Example 2, the methyl, ethyl, tert-butyl, and 2-ethylhexyl esters of 15- methyl-PGE l5-methyl-l5(R)-PGE, l5-ethyl-PGE IS-ethyll5(R )-PGE,, l5-methyl-PGE lS-methyll5(R)-PGE l5-ethyl-PGE l5-ethy1-l5(R)-PGE l5- methyl-PGE l5-methyl-l5(R)-PGE l5-ethyl-PGE l5-ethyll 5( R)-PGE IS-methyI-dihydro-PGB, l5 methyl-dihydrol 5(R)-PGE, l5-ethyl-dihydro-PGE, l5-ethyl-dihydro-l5(R)-PGE, and the racemic form of 9 each of those are each dehydrated to the corresponding IS-methyl or l-ethyl prostaglandin A ester.

We claim: 1. An optically active compound of the formula:

or a racemic compound of that formula and the mirror image thereof, wherein R, is hydrogen, alkyl of one to 8 carbon atoms, or a pharmacologically acceptable cation, wherein R is methyl or ethyl, and wherein the side-chain hydroxy is in S or R configuration.

2. An optically active compound of the formula:

or a racemic compound of that formula and the mirror image thereof, wherein R, is hydrogen, alkyl of one to 10 8 carbon atoms, or a pharmacologically acceptable cation, and wherein R is methyl or ethyl.

3. An optically active compound of the formula:

or a racemic compound of that fon'nula and the mirror image thereof, wherein R, is hydrogen, alkyl of one to 8 carbon atoms, or a pharmacologically acceptable cation, and wherein R is methyl or ethyl.

4. IS-Methyl-PGA, an optically active compound according to claim 2 wherein R, is hydrogen and R is methyl.

5. lS-Methyl-PGA, methyl ester, an optically active compound according to claim 2 wherein R, and R are both methyl.

6. l5-Methyl-15(R)-PGA an optically active compound according to claim 3 wherein R, is hydrogen and R, is methyl.

7. 15-Methyl-l5(R)-PGA methyl ester, an optically active compound according to claim 3 wherein R, and R are both methyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT N0. 3 ,9l 9,286

DATED I November ll l975 INVENTOR( 1 Gordon L Bundy et al ll is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1 line 24: "Pharmacol Rec. 20," should read --Pharmacol Rev. 20,--.

Column 2, line 36: "the work "racemic" "should read --the word "racemic"--.

Column 2-3, lines 68-l Y is cis-CH= \CH-," should read --Y is cis-CH=CH-,--.

Column 8, line 27: "The, additional" should read --Then,

additional".

Column 8, line 38: "procedure of Example l should read --procedure of Example 2,--.

Column 8, lines 40-4l l5-ethyl-d1'hydro-PGD are" should read --l5-ethyl-d1'hydro-PGE are--.

Signed and Scaled this Twenty-seventh D f December 1977 {SEAL} RUTH C. MASON LUTRELLE F. PARKER Arresting 0 wer Acting Commissioner of Parents and Trademarks 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FROMULA:
 2. An optically active compound of the formula:
 3. An optically active compound of the formula:
 4. 15-Methyl-PGA2, an optically active compound according to claim 2 wherein R1 is hydrogen and R2 is methyl.
 5. 15-Methyl-PGA2 methyl ester, an optically active compound according to claim 2 wherein R1 and R2 are both methyl.
 6. 15-Methyl-15(R)-PGA2, an optically active compound according to claim 3 wherein R1 is hydrogen and R2 is methyl.
 7. 15-Methyl-15(R)-PGA2 methyl ester, an optically active compound according to claim 3 wherein R1 and R2 are both methyl. 